Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[C:35]([N:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:24]([O:26][CH3:27])=[O:25])=[CH:12][CH:11]=3)[CH2:19][CH2:20]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNCC3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(C(C)=O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(piperazin-1-yl)quinoxaline-6-carboxylate (180 mg, 0.49 mmol) in dichloromethane (10 ml) was added Et3N (59 mg, 0.59 mmol) and then acetyl chloride (39 mg, 0.59 mmol) was added dropwise. The resulting solution was stirred for 1 hour at room temperature and then quenched by the addition of ice-water (100 ml) and extracted with dichloromethane (3×15 ml). The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-(4-acetylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (103 mg, 51%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)[CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:29][C:30]1([CH3:34])[CH2:33][O:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][C:30]1([CH2:34][O:1][C:2]2[CH:3]=[C:4]([C@H:8]3[CH2:10][C@@H:9]3[C:11]([NH:13][C@@H:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=3)[CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=2)[CH2:33][O:32][CH2:31]1
Reactant: CC1(CCl)COC1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1cccc(O)c1)c1ccc(OCC(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1cccc(OCC2(C)COC2)c1)c1ccc(OCC(F)(F)F)cn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 49.1 %

Procedure:
A mixture of (1S*,2S*)-2-(3-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (15 mg, 0.039 mmol), 3-(Chloromethyl)-3-methyloxetane (24 mg, 0.197 mmol) and potassium carbonate (27 mg, 0.197 mmol) in DMF (2 mL) was heated at 70° C. with stirring for 15 hours. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 8.9 mg (49% yield) of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:10]=[N:11][C:12]([NH:15][CH3:16])=[CH:13][CH:14]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl.O>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([C:38]([N:15]([CH3:16])[C:12]2[N:11]=[CH:10][C:9]([CH2:8][N:6]3[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]3)=[CH:14][CH:13]=2)=[O:39])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)nc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 64.4 %

Procedure:
To 1,1-dimethylethyl (2S)-2-methyl-4-{[6-(methylamino)-3-pyridinyl]methyl}-1-piperazinecarboxylate (D96) (0.150 g, 0.469 mmol) and triethylamine (0.098 mL, 0.703 mmol) in DCM (7 mL) under argon was added 6-chloro-3-pyridinecarbonyl chloride (0.099 g, 0.562 mmol). The mixture was stirred at room temperature for 0.3 h then diluted with DCM and water. The organic layer was dried and concentrated to give the crude product which was purified by column chromatography. Elution with EtOAc/DCM gave the title compound as a white colourless gum (0.139 g). δH (CDCl3, 400 MHz) 8.33 (1H, d), 8.19 (1H, d), 7.70 (1H, dd), 7.57 (1H, dd), 7.23 (1H, d), 6.86 (1H, d), 4.20 (1H, br.s), 3.82 (1H, d), 3.58 (3H, s), 3.49 (1H, d), 3.37 (1H, d), 3.08 (1H, td), 2.70 (1H, d), 2.49 (1H, d), 2.16 (1H, dd), 2.04 (1H, m), 1.46 (9H, s), 1.19 (3H, d). MS (ES): MH+ 460/462
Reaction SMILES: [CH:1]([NH:4][C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2].[CH2:13]=O.[H][H]>C(O)C.[Pd]>[CH:1]([N:4]([CH3:13])[CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=O
Reactant: CC(C)C[C@H](NC(C)C)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)CC(C(=O)O)N(C)C(C)C
Yield: 89 %

Procedure:
A mixture of (S)-2-isopropylamino-4-methyl-pentanoic acid (70.86 g, 0.41 mol, Example 19, Step A) and aqueous HCHO (94 mL of 37.2%) was agitated in an atmosphere of hydrogen (pressure, 47-52 psi) at 50° C. in absolute ethanol (1.5 L) in the presence of Pd/C (20%, 5 g) until the absorption of hydrogen almost ceased. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to dryness. One hundred milliliters of water was added and concentrated to dryness, and this operation was repeated twice to remove most of HCHO. Absolute ethanol (100 mL) was then added and concentrated to dryness to remove residual water. The white solid collected was triturated with acetone. Filtration and drying under vacuum gave 69.39 g (89%) of the desired product as a white solid; mp 159-160° C. APCI-MS m/z 188.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:32]([Mg]Cl)[CH3:33].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH2:32][CH3:33])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC[Mg]Cl
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) in THF (10 ml) was added dropwise a solution of ethyl magnesium chloride in THF (2M, 0.61 ml) and the mixture was stirred at room temperature for 10 min. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=1:2), followed by crystallization from ethyl acetate-hexane to give the title compound (250 mg).
Reaction SMILES: [I:1]I.[C:3]1([CH2:9][CH2:10]O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl>[C:3]1([CH2:9][CH2:10][I:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: II
Reactant: OCCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
Iodine (12.0 g, 47.4 mmol) was added in one portion to a solution of 2-phenylethanol (5.11 g, 36.5 mmol), triphenylphosphine (11.47 g, 43.8 mmol) and imidazole (3.48 g, 51.04 mmol) in dichloromethane (250 mL) at 0° C. The resulting mixture was allowed to warm slowly to rt and stir overnight, then was transferred to a separatory funnel and washed with water (2×250 mL), saturated aqueous Na2S2O3 (2×100 mL), water (100 mL), and brine (100 mL). The organic phase was dried over MgSO4, filtered and concentrated to a colorless oil that contained a large amount of white solid. The mixture was treated with heptane (2×50 mL) and was filtered. The filtrate was concentrated and the resulting material was again treated with heptane (2×50 mL) and filtered. The filtrate was concentrated to provide 2-phenylethyl iodide as a clear colorless oil (1.74 g, 19%) that contained a trace amount of triphenylphosphine oxide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].[NH2:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][C:27]([F:30])([F:29])[F:28])[N:19]=1>ClCCCl>[CH3:25][O:24][C:22]1[N:21]=[C:20]([O:26][C:27]([F:30])([F:28])[F:29])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:12])=[O:13])=[O:16])[N:23]=1
Reactant: COc1nc(N)nc(OC(F)(F)F)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC(F)(F)F)n1
Temperature: 22 °C
Reaction time: 12 h

Procedure:
3.6 g (0.015 mol) of 2-carbomethoxybenzenesulfonyl isocyanate in 4 ml of 1,2-dichloroethane were added over the course of 5 minutes to a stirred mixture of 3.15 g (0.015 mol) of 2-amino-4-methoxy-6-trifluoromethoxy-1,3,5-triazine and 150 ml of 1,2-dichloroethane at 22° C., and the mixture was stirred at 22° C. for 12 hours. It was then concentrated under reduced pressure and crystallized using 1:1 methyl tert-butyl ether/ petroleum ether, and the product was filtered off with suction and washed with petroleum ether to yield 5.1 g (75.4% of theory) of the title compound of melting point 149° C. (decomposition).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][S:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9]>C(OCC)C>[CH3:4][S:5][C:6]1[CH:7]=[C:8]([NH:9][C:2]#[N:1])[CH:10]=[CH:11][CH:12]=1
Reactant: CSc1cccc(N)c1
Reactant: N#CBr
Solvent: CCOCC
Product: CSc1cccc(NC#N)c1
Temperature: 24 °C
Reaction time: 12 h
Yield: 31.8 %

Procedure:
A solution of cyanogen bromide (1.42 g, 13.4 mmol) in anhydrous diethyl ether (8 mL) was added slowly to a stirred solution of 3-(methylthio)aniline (2.72 mL, 21.4 mmol) in anhydrous diethyl ether at 4° C. After the addition, the reaction mixture was stirred at 24° C. for 12 hours and became a brown solution with a white precipitate. The precipitate was filtered off; the filtrate was washed with aqueous HCl (1 M, 3×15 mL) in ether and the organic layer extracted with brine (10 mL). Then the ether solution was dried over MgSO4, filtered, and concentrated in vacuo to yield a thick liquid. The crude product was further purified by column chromatography (SiO2, a gradient of hexanes/CH2Cl2/EtOAc) to afford 3-(methylthio)phenyl cyanamide (0.7 g, 49% yield) as a white solid: m.p. 64-65° C.;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([CH3:10])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc(N)cc1C(F)(F)F
Product: Cc1ccc(Nc2nc(Cl)ncc2F)cc1C(F)(F)F

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-methyl-3-trifluoromethylaniline were reacted to provide 2-chloro-5-fluoro-N4-(4-methyl-3-trifluoromethylphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.10 (d, 1H, J=3.0 Hz), 7.85-7.78 (m, 2H), 7.33 (d, 1H, J=9.3 Hz), 6.96 (bs, 1H), 2.48 (d, 3H, J=1.2 Hz); 19F NMR (282 MHz, CDCl3): −17641, −44541; LCMS: purity: 97%; MS (m/e): 306(MH+).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[C:4](=[O:5])[O:3]1>O1CCCC1.[Pd]>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:2]([OH:1])[O:3][C:4]2=[O:5]
Reactant: O=C1OC(O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2c1C(O)OC2=O

Procedure:
10 g of 3-hydroxy-4-nitro-phthalide are dissolved in 100 ml of tetrahydrofuran and hydrogenated at atmospheric pressure and at 20°-35° C. after adding 1 g of palladium on barium sulphate (5%). The catalyst is filtered off and the filtrate is concentrated. The evaporation residue is stirred with ether and filtered with suction. 5.8 g (68.5% of theory) of a colorless substance of melting point 280°-285° C. (dec.) are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=1)(=[O:30])=[O:29])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 124 mg of 4-butoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.98 (t, 3H, J=7.6 Hz), 1.45 (m, 2H), 1.72 (m, 2H), 3.79 (t, 2H, J=6.6 Hz), 6.66 (d, 2H, J=8.8 Hz), 7.31 (d, 1H, J=2.8 Hz), 7.35–7.42 (m, 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.53–7.60 (m, 3H), 7.75 (d, 1H, J=8.8 Hz), 9.62 (s, 1H). MS: m/z 444.9 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18](Cl)[C:17]=1[Cl:27])[OH:15].C(N(CC)CC)C>[C].[Pd].CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[CH:18][C:17]=1[Cl:27])[OH:15]
Reactant: COc1cc(C)c(C(O)c2c(C(F)(F)F)cnc(Cl)c2Cl)c(OC)c1OC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(C)c(C(O)c2c(Cl)cncc2C(F)(F)F)c(OC)c1OC
Reaction time: 4 h
Yield: 69.9 %

Procedure:
2.1 g of 5% palladium carbon was added to a methanol 200 ml solution of 24.8 g (58.1 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(2,3-dichloro-5-trifluoromethyl-4-pyridyl)methanol obtained in step (a) and 9.50 ml (68.2 mmol) of triethylamine, followed by stirring under hydrogen atmosphere for 4 hours. The mixture was subjected to filtration, 50 ml of water was added thereto, and methanol was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 15.9 g (yield 70%) of (2,3,4-trimethoxy-6-methylphenyl)(3-chloro-5-trifluoromethyl-4-pyridyl)methanol (m.p. 102-105° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH2:11].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:21][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]1=[O:13]
Reactant: NCCCc1ccccc1Br
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCc1ccccc1Br
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A mixture of 3-(2-bromophenyl)-propylamine (6.9 g, 30 mmol), 2-bromomethyl-benzoic acid methyl ester (6.42 g, 30 mmol), and K2CO3 (6.91 g, 50 mmol) in toluene (100 mL) was heated at reflux with stirring for 2 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(2-bromophenyl)-propyl]-2,3-dihydroisoindol-1-one (5.7 g, 58%). GC/MS gave: m/z (rel.int.) 331 (M+, 3), 329 (M+, 3), 250 (42), 147 (82), 146 (100) 119 (27), and 91 (47). 1H NMR (300 MHz, CDCl3): δ 2.00 (dt, 2H), 2.80 (t, 2H), 3.74 (t, 2H), 4.40 (s, 2H), 7.04 (dt, 1H), 7.19-7.27 (m, 3H), 7.43-7.53 (m, 3H), 7.76 (dd, 1H). 13C NMR (300 MHz, CDCl3): δ 28.7, 33.7, 42.1, 50.0, 122.8, 123.8, 124.4, 127.7, 127.9, 128.1, 130.6, 131.3, 132.9, 133.1, 140.8, 141.3, 168.7.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[CH:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[C:19]2=[N:18][CH:17]=[CH:16][CH:15]=[C:14]2[CH:13]=[CH:12]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: OCCc1ccc(I)cc1
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OCCc1ccc(-n2ccc3cccnc32)cc1
Temperature: 80 °C
Yield: 88.1 %

Procedure:
A mixture of 1.24 g (5 mmol) of 2-(4-iodophenyl)ethanol, 0.62 g (5.25 mmol) of 7-azaindole, 2.33 g (11.0 mmol) of potassium phosphate, 0.082 g (1.0 mmol) of N,N′-dimethylethylenediamine and 0.095 g (0.50 mmol) of cuprous iodide in 4 ml of toluene is heated at 80° C. overnight with thorough stirring under an argon atmosphere. The mixture is cooled to ambient temperature and diluted with 150 ml of ethyl acetate and 50 ml of water. After the phases have settled and been separated, the organic phase is washed with 25 ml of water and 25 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 70/30 then 60/40 and 50/50 mixture of cyclohexane and ethyl acetate, to give 1.05 g of product in the form of an oil.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)(=O)C.I(C1C=CC=CC=1)=O.B(F)(F)F.CCOCC.[CH2:26]([O:28][C:29](=[O:38])[CH2:30][C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:32])C>CO>[CH3:26][O:28][C:29](=[O:38])[CH:30]([O:3][CH3:1])[C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:32]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)C1CCCC1
Agent: FB(F)F
Agent: O=Ic1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(OC)C(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared using a method analogous to that described in Tetrahedron 1998, 44, 1603-1607: To a suspension of iodosobenzene diacetate (5.2 g, 16.3 mmol) in MeOH (40 mL) was added BF3.OEt2 (2.1 mL, 16.3 mmol). The resulting mixture was added to 3-cyclopentyl-3-oxo-propionic acid ethyl ester (3.0 g, 16.3 mmol) and stirred at rt overnight. The mixture was concentrated to half the total volume, quenched with satd. aq. NaHCO3, and extracted with CHCl3 (2×). The combined organic layers were dried and concentrated and the crude residue purified (EtOAc/hexanes) to yield a colorless oil (1.5 g, 43%). 1H NMR (MeOD): 4.4 (s, 1H), 3.8 (s, 3H), 3.5 (s, 3H), 3.3-3.2 (m, 1H), 1.9-1.5 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:15]1([S:21]([N:24]2[C:32]3[C:27](=[N:28][C:29]([Cl:33])=[CH:30][CH:31]=3)[CH:26]=[C:25]2[CH2:34]Br)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:34][C:25]2[N:24]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[C:32]3[C:27](=[N:28][C:29]([Cl:33])=[CH:30][CH:31]=3)[CH:26]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: O=S(=O)(c1ccccc1)n1c(CBr)cc2nc(Cl)ccc21
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2cc3nc(Cl)ccc3n2S(=O)(=O)c2ccccc2)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using 1-benzenesulfonyl-2-bromomethyl-5-chloro-1H-pyrrolo[3,2-b]pyridine in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is purified by column chromatography eluting with a gradient of 15% EtOAc/hexanes to 50% EtOAc/hexanes to give the title compound as a beige solid.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1>>[N:24]1([CH2:23][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCn1nnc2ccccc21
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cn2nnc3ccccc32)c1
Yield: 36.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 1-chloromethyl-1H-benzotriazole were reacted by the same way with the example 1 to obtain the titled compound (152 mg, yield: 36.4%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[OH:19])=[CH:13][CH:12]=3)=[CH:6][N:5]2[CH:21]=1.[CH2:22](NC(=O)O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:33]1([C:36]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:19])[O:20][CH2:22][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:21]=2)=[O:37])[CH2:35][CH2:34]1
Reactant: Nc1cn2cc(Oc3ccc(NC(=O)O)cc3)ccc2n1
Reactant: O=C(O)NCc1ccccc1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of benzylcarbamate {4-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}carbamate (8.7 g, 22.2 mmol) in N,N-dimethylacetamide (70 mL) was added cyclopropanecarbonyl chloride (2.21 mL, 24.4 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (=1/1) and collected by filtration to give the title compound (8.5 g, 87%) as a thin-brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH:7](=O)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17](O)(=[O:28])[CH2:18][C:19](CC(O)=O)([C:21]([OH:23])=[O:22])O.[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[C:2]([O:4][C:17](=[O:28])[CH2:18]/[C:19](=[CH:7]\[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[C:21]([OH:23])=[O:22])([CH3:5])([CH3:3])[CH3:1]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)[O-]
Reactant: O=CCCc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C/C(=C\CCc1ccccc1)C(=O)O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 74785.5 %

Procedure:
A solution of 3-(diethoxyphosphoryl)succinic add 1-tert-butyl ester (100 g, 0.32 mol) in THF 300 ml) was added dropwise over 15 min to a stirred solution of potassium tert-butoxide (110 g, 0.98 mol) in THF (300 ml), between −10 and −5° C., under nitrogen. The mixture was stirred at −10° C. for 15 min and then a solution of hydrocinnamaldehyde (46.8 g, 0.35 mmol) in THF (100 ml) was added dropwise over 15 min, between −13 and −8° C. The mixture was stirred at −10° C. for 30 min and then a solution of citric acid (111 g, 0.58 mol) in demineralised water (500 ml), and ethyl acetate (500 ml), were added. The pH was adjusted to pH 4 with aqueous sodium hydroxide solution (50%) and the phases were separated. The aqueous fraction was washed with ethyl acetate (500 ml) and the combined organic fractions were washed with saturated sodium bicarbonate solution (500 ml), citric acid solution (10%, 500 ml) and demineralised water (500 ml) and then concentrated in vacuo. The resulting solid was slurried in cyclohexane (470 ml) for 1 hour and then the mixture was filtered. The residue was washed with cyclohexane (2×50 ml) and dried in vacuo to leave the title compound as a colourless solid (76 g, 81%).